The long-term goal of this project is to increase non-small cell lung cancer (NSCLC) tumor control without increasing treatment toxicity by adapting therapy to the individual patient's response. This goal will be carried out through two specific aims. Aim 1 is to conduct a pilot study to decrease toxicity by adapting therapy to the uninvolved lung and esophagus while continuing to adapt therapy to the tumor for patients with Stage II/III NSCLC cancer. We have recently completed a phase II study in which we targeted FDG avid regions midtreatment with a high dose of radiation and achieved a >20% improvement in local control over standard dose (60 Gy), although toxicity was greater. With maturing of response based predictive models for treatment toxicity, we propose a pilot study in which we will continue to adapt therapy midtreatment to intensify dose to the residual FDG avid tumor, and we will use: 1) V/Q SPECT-CT scanning to avoid functional lung; 2) FDG-PET-CT to adapt the risk of esophageal injury; and 3) reduce dose in patients who are unusually sensitive to radiation (by measuring TGFbetal and IL-8). We hypothesize that by adapting radiation therapy to the uninvolved lung and esophagus, we can maintain the dose to the FDG-avid tumor while causing no greater overall toxicity than expected from standard therapy (60 Gy uniformly delivered to the tumor). Aim 2 is to conduct a phase II randomized trial to compare standard therapy to therapy that adapts treatment to the individual patient's tumor and uninvolved tissue response. This aim will use the methodology developed from aim 1 for the experimental arm that fully adapts treatment based on intensifying treatment to the FDG avid tumor while limiting the toxicity of uninvolved lung and esophagus to be no greater than that anticipated to be caused by standard therapy. This will be accomplished by 1) avoiding functioning lung at the start of treatment; 2) by replanning midtreatment based on adapting to the response of the tumor and of the uninvolved lung and esophagus and 3) reducing dose to the most sensitive patients. This arm will be compared in a randomized phase II trial to a standard arm (60 Gy) (both arms with the same chemotherapy). We hypothesize that treating patients with adaptive radiation therapy based on the tumor and normal organ responses assessed during treatment will produce superior tumor control at no greater toxicity than the standard arm of 60 Gy uniformly delivered to the tumor. The impact o f t h i s work is that it will develop a new paradigm for radiation oncology in which treatment is optimized by adapting therapy to the individual patient response, rather than based on the average patient.